Antinociception (analgesia) and antagonists to this activity by recently developed opioidmimetic substances was determined in comparison to morphine (mu-opioid receptor agonist) and deltorpin (delta-opioid agonist) to assess their mode of action using mice models. The antinociception profile paralleled that of the in vitro functional pharmacological data GPI (guinea-pig ileum) and MVD (mouse vas deferens) and reflected the opioid-receptor binding affinity in addition to the assessment of G-protein interaction using the GTP-gamma-S assays, which represent an in vitro analysis of the pharmacological preparations. A series of novel Dmt-Tic pharmacophoric drugs or protodrugs exhibited antagonism in vitro and in vivo using the hot-plate (supraspinal effects, the central nervous system) and tail-flick test (spinal effects). The control compounds exhibited central (CNS) mediated analgesia and were orally bioavailable opioidmimetics. Interestingly, N,N-dimethyl-Dmt-Tic-NH-adamantane and H-Dmt-Tic-NH--tert-butyl derivatives inhibited tolerance to morphine in mice, which suggests that the multidrug resistance P-glycoprotein 1 was involved due to their inhibition in vitro of Pg-1. Other Dmt-Tic compounds, such as MZ-2, in particular (patent application pending) prevents the formation of tolerance to morphine like the N-allyl-Dmtendomorphin analogues, which are neutral opioid antagonists following morphine or alcohol treatment. Furthermore, the elimination of tolerance occurred without the severe side-effects seen with both naloxone and naltrexone, a FDA approved drug for the treatment of alcoholism. N-allyl-Dmtendomorphin-1 and -2 derivatives were highly potent mu-opioid antagonists as demonstrated by intracerebroventricular administration in mice: they effectively inhibited morphine antinociception similar to naloxone, a standard mu-opioid receptor antagonist. Both compounds effectively and completely eliminated withdrawal symptoms following either acute or chronic morphine addiction in mice. In addition, MZ-2 decreased food intake in ob/ob mice, altered the levels of several key indicators of obesity in the clinical analyses of blood samples and elevated bone mineral density;the data portend an application of MZ-2 in fighting obesity in human populations.